Continuous DNA double strand break (DSB) formation, followed by the activation of the DNA damage response (DDR), occurs in both premalignant conditions and established cancers of the epithelial lineage. However, in normal tissues and in precancerous settings, robust senescence and apoptotic responses are mounted, the so-called ‘tumorigenesis barrier’, that thwarts the progression to malignancy (Halazonetis et al., 2008). During the transition toward cancer, functional inactivation of the tumor suppressor TP53 (p53) suppresses the apoptotic and senescence responses triggered by DSBs and DDR, thereby allowing unfettered tumor cell growth and survival. Hence, in epithelial tumors, p53 loss represents the foremost mechanism by which tumor cells acquire unconstrained genomic instability that allows for the acquisition of additional, favorable mutations and genomic rearrangements, which ultimately promote cancer growth (Halazonetis et al., 2008).
The role of DDR and p53 inactivation is largely unexplored in hematological disorders, albeit evidences of ongoing DNA damage are starting to emerge also in this group of diseases. In a mouse model of acute myeloid leukemia driven by MLL (MLL-AML), activation of the MLL-ENL oncogene induced phosphorylation of histone variant H2A.X (γ-H2A.X) and activation of the DDR through phosphorylation of ATR and ATM (pATR and pA™) kinases, followed by senescence. Bone marrow biopsies from 3 MLL-rearranged AML patients were positive for pATR, pATM and γH2A.X, suggesting that MLL-ENL is associated with a similar response also in humans (Takacova et al., 2012). Variable levels of γ-H2A.X and pATM have been reported in AML and myelodysplastic syndromes as well (Boehrer et al., 2009). Importantly, the prototype of ongoing DNA damage in a hematological disorders is multiple myeloma (MM), since γ-H2A.X and pATM have been detected both in the premalignant condition MGUS (Monoclonal Gammopathy of Undetermined Significance), as well as in almost all MM patient cells and cell lines (Walters et al., 2011). However, unlike epithelial cancers, p53 mutations are relatively rare in hematological disorders and appear late during the course of these diseases. In MM for example, p53 mutations and deletions are absent in MGUS, rare in newly diagnosed patients (5-10%), and considered to be a late event in disease progression, being present in 10-20% of patients with relapsed and refractory MM (Xu-Monette et al., 2012). Mutations or loss-of-heterozygosity of ATM and ATR, commonly reported in other cancers as means to overcome DDR-associated apoptosis, are even rarer in MM, and no mutations affecting CHK2 and CHK1 have been identified (Chapman et al., 2011). Therefore, the model proposed for epithelial cancers, whereby p53 mutations allow premalignant cells to overcome senescence and apoptosis despite intense DNA damage to become full-blown tumor cells, might not hold true for hematological disorders.
A pathway downstream of ATM/ATR and alternative to p53 has been described, which is activated after DSB and able to induce apoptosis (Baskaran et al., 1997; Kharbanda et al., 1995; Shafman et al., 1997; Yuan et al., 1996; Yuan et al., 1997). It is centered on the proto-oncoprotein ABL1, commonly translocated in chronic myeloid leukemia (CML) and in acute lymphoblastic leukemia (ALL). Imatinib, a kinase inhibitor that reversibly binds to the ATP kinase pocket of ABL1 and blocks its function, induces apoptosis in the leukemic cells with this translocation and has transformed the treatment and outcome of affected patients since its introduction in the clinic. On the other hand, treatment of cell lines with high-dose DNA damaging agents such as doxorubicin, etoposide and cisplatin results in relocalization of ABL1 from cytoplasm to the nucleus, where it elicits an apoptotic response; therefore, in this context ABL1 acts as a pro-apoptotic gene. Importantly, to date, ABL1 relocalization in the nucleus has been demonstrated only in in vitro settings (tumor cell lines) and has been reported to occur exclusively after drug-induced DNA damage. Therefore, its functional and potential clinical relevance is unknown.
Multiple myeloma is the second most frequent hematological cancer after non-Hodgkin's lymphoma and is characterized by the accumulation of neoplastic plasma cells in the bone marrow. Despite recent advances in therapies and improved patient outcomes, MM remains an incurable cancer with a median survival of 6 years (Palumbo and Anderson, 2011), hence novel therapies are urgently needed.